Our long-term goal is to develop strategies to prevent and treat chronic graft-versus-host disease (cGVHD) using murine preclinical models. cGVHD has emerged as one of the primary causes of morbidity and mortality following allogeneic HSCT. Whereas acute GVHD rates have decreased with more intensive GVHD preventive agents and use of umbilical cord blood as a source of donor cells, significant cGVHD rates unexpectedly have remained largely unchanged. Moreover, peripheral blood stem cell grafts have been associated with an increased overall risk of cGVHD. As such, cGVHD has emerged as one of the primary causes of morbidity and mortality following allogeneic hematopoietic stem cell transplantation. Unfortunately and in rather striking contrast to aGVHD, little progress has been made in cGVHD prevention and therapy. We have generated a bona fide cGVHD model of bronchiolitis obliterans (BO) using cvclophosphamide and total body irradiation. Because cGVHD has a later onset than typical aGVHD, a lower T cell number was infused to permit long-term and continued antigenic stimulation of donor anti-host alloreactive T cells. BO was convincingly demonstrated at late times by multiple parameters including obstructive disease with fibrosis and restrictive lung dysfunction by pulmonary function tests. BO mice had skin, salivary gland, hepatic, and intestinal cGVHD. In contrast to aGVHD, B cells were present in multiple organs including the lung and low serum anti-host alloAb levels were present. Two specific aims are proposed. Aim 1: To define the critical factors and mechanisms responsible for multiorgan system cGVHD and BOgeneration. Aim 2. To devise new interventional strategies to prevent or treat early manifestations of cGVHD with BO. We hypothesize that these prophylactic and early therapeutic interventional approaches will be effective in reducing the severity of BO and cGVHD if given prior to the onset of severe fibroproliferative disease. RELEVANCE (See instructions): Public Health Benefits. Our goal is to develop clinically relevant approaches to prevent and treat cGVHD which is a major source of moribity and mortality post-transplant, limiting the more widespread use of this methodology for the treatment of malignant and non-malignant disorders.